The mechanisms underlying cognitive and motor impairments of Alzheimer's Disease (AD) are undoubtedly diverse and multifactorial, reflecting the complex neuropathology of this degenerative disease. At one level of analysis, however, such impairments may be related to abnormalities in neuronal signaling and communication, and ameliorative therapeutic strategies developed around this theme, such as has been the case for anticholinesterase treatment to counteract deficits in cholinergic tone. Neurotransmitter/receptor interactions, however, are but one component of the signalling cascade. Second messenger systems and ion channel-mediated electrical excitability also play important roles in this process. Interestingly, several lines of investigation have revealed changes in the prototypical voltage-gated neuronal sodium channel activity associated with very aged animals and with Down syndrome, whose victims invariably develop AD-type illness in the third/fourth decade of life. These considerations, and others, provide the impetus to undertake a pilot study concerning these sodium channels and AD, the relationship of which is completely unexplored. Specifically, we will test the hypothesis that hippocampal voltage-gated sodium channel mRNA expression is altered in AD compared to normal, age- matched controls. To accomplish this, oligonucleotide probes corresponding to two distinct (and possibly more) human brain sodium channel subtypes (a- subunit), recently cloned in this laboratory, will be prepared and their subtype specificity determined. Using techniques of both Northern slot blot analysis and in situ hybridization, the relative amounts and the ratio of subtype mRNA will be quantitated in postmortem hippocampal tissue from AD and normal brain samples provided by the Neuropathology Core. Rejection of the null hypothesis in this study should prompt additional research concerning these changes, their functional consequences, and the implications for the development of new ameliorative strategies.